Alzheimer's disease (AD) is the most common cause of dementia. According to the WHO, in the year 2006 the number of people suffering dementia amounted to 37 million worldwide, 18 million of which were Alzheimer's patients. In this sense, the number of patients is expected to double in the next 25 years, reaching 34 million in 2025. In Spain alone it is estimated that over half a million people currently suffer AD (Mount & Downtown, Nat Med 2006; 12[7]: 780-4).
The costs associated with this disease are proportionally high. In 2005, health costs for Alzheimer's disease and other dementias in the 27 countries forming the European Union were estimated to be in 130,000 million Euros, about 21,000 Euros per patient and year. The total cost derived from caring for Alzheimer's patients in the United States in 2005 was calculated to be 91,000 million dollars, detecting an increase in medical expenses associated with the disease, which exceeded 160,000 million dollars in 2010 (Mount & Downtown, Nat Med 2006; 12[7]: 780-4).
Based on the foregoing reasons, AD and diseases associated with aging such as cognitive deficits or dementias have become a major problem worldwide. However, there are no efficient drugs that prevent or impede neurodegenerative diseases (ND), therefore the search for and validation of new neuroprotective compounds preventing neuronal damage have become a necessity, especially taking into account that the pathophysiological mechanisms thereof have yet to be clarified. Neurodegenerative pathologies are a consequence of neuronal death and of the subsequent loss of brain mass, a consequence of the absence of neurons in specific areas of the brain. For this reason, one of the valid strategies for the treatment and/or prevention of ND is the search for drugs impeding neuronal death, i.e., they are neuroprotective drugs. However, the drugs used until now for AD have been symptomatic, and do not prevent disease progression or onset. Until now there have been two types of drugs on the market: acetylcholinesterase (AChE) inhibitors and memantine, an NMDA (N-methyl-D-aspartic acid) glutamatergic receptor inhibitor. Current therapeutic options for AD are based on inhibiting acetylcholinesterase with drugs such as donepezil, galantamine or rivastigmine, or on the capacity of memantine to antagonize the NMDA receptor. Nevertheless, it has been proven that the use of rivastigmine does not stop or slow down the progression of mild cognitive impairment (MCI) or of AD (Feldman et al. Lancet Neurol 2007; 6[6]: 501-12), whereas the use of donepezil only shows modest short-term benefits, but with the drawback of presenting significant side effects (Birks and Flicker, Cochrane Database Syst Rev 2006; 3: CD006104). According to the American Alzheimer's Association, the emergence of drugs that delay disease onset by only 5 years would save 50,000 million dollars in the United States alone. In this sense, the use of preventive strategies, such as intervention in mild cognitive impairment (MCI) processes would be a valid alternative.
MCI, also known as incipient dementia or isolated memory impairment, is one of the prior stages associated with AD and other dementias. MCI is recognized as a risk factor of AD; it affects about 30 million people worldwide and is considered a first step towards AD, where between 10 and 15% of individuals with MCI progress to AD each year (Grundman et al. Arch. Neurol 2004; 61[1]: 59-66). Despite the significant prevalence of MCI and of the high likelihood of patients to progress to a dementias, there is currently no treatment or therapy for this clinical condition, whereby the use of antioxidants or anti-AD drugs is recommended for the treatment of MCI. So there are currently no drugs for treating MCI, and current anti-AD drugs offer few benefits to patients which temporarily delay (by one year in a best-case scenario) some symptoms of the disease but do not prevent their progression.
Due to the very limited success of drugs against NDs, new lines of research have opened up. Search strategies for finding for new chemical entities (NCE) based on natural biodiversity stand out among them. In fact, the search for bioactive compounds against different pathologies is one of the central themes of natural product chemistry. Massive search strategies for finding compounds and extracts based on different biological sources, among which microorganisms can be found, have recently started to be applied. The search for active biomolecules therefore requires the isolation and culture of microorganisms that produce compounds from different environments. In fact, more 20,000 of the 250,000 bioactive metabolites that are calculated to exist are produced by microorganisms. Filamentous fungi, single-cell bacteria and actinomycetes are the most prolific groups when it comes to producing such compounds. Approximately only 1% of these compounds, about 160, are used directly in human and animal medicine and in agriculture. This ratio (0.2-0.3%) is, however, much higher than that attained by the pharmaceutical industry by means of new chemical entities obtained by synthesis (0.001%). Between the years of 2005 and 2007 alone, 19% of the drugs launched on the market were natural products or products derived from natural products. The chemical variety of these metabolites is enormous because it depends on the microorganism, on the composition of the culture medium and on the conditions under which said culture is performed.
In this sense, formylated xanthocillin analogues with a single substituent in each aromatic ring obtained by mixed fermentation of A. fumigatus with S. peucetis have been described (Zuck et al., J. Nat. Prod. 2011, 74, 1653-1657), which demonstrated antitumor activity using the 60 NCI-60 cell line panel. Two of these compounds showed activity against some cell lines (of lung cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer and leukemia), whereas the remaining compounds were inactive. The activity of one of the two compounds against Escherichia coli, Candida albicans, Staphylococcus aureus, Burkholderia thailandesis and Fusarium pallidoroseum was evaluated, but no activity was shown in said assays.
It has also been proven that the formylated xanthocillin analogue isolated from Cordyceps brunnearubra BCC 1395, as well as the hexamethylated and hexaacetylated compounds obtained by methylation and acetylation, show activity against the malaria parasite Plasmodium falciparum, cytotoxicity against breast cancer cells, while lacking activity against human oral epidermoid carcinoma and lung cancer cells and non-cancerous Vero cells (Isaka et al., J. Nat. Prod. 2007, 70, 656-658).
Nevertheless, neuroprotective activity has not been proven for any of these compounds isolated from the mentioned microorganisms.